A gene is considered a candidate gene for type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. In the past year we have directly sequenced and genotyped all detected variants in more than 20 physiologic candidate genes for associations with BMI or diabetes. Genotyping was performed in two large population based samples of individuals collected from the Gila River Indian Community. A type 2 diabetes gene (KCNQ1) identified in a Chinese population appears to have a significant role in determining type 2 diabetes, obesity, and early insulin secretion response in Pima Indians. These variants exhibit parent of origin effects, such that the variants have different effects on disease risk if they were inherited maternally or paternally. Another gene, Sirt1, has previously been implicated in the pathogenesis of obesity and, to a lesser degree, type 2 diabetes. Our study in Pima Indians identified DNA variants that were associated with increased risk for type 2 diabetes, where this risk was likely due to impairment of glucose-stimulated insulin secretion. We also identified a significant gender interaction with type 2 diabetes, which has not been previously reported. In an expression analysis of adipose biopsies from Pima Indians, Sirt1 expression levels were strongly correlated with the donors BMI;however, DNA variants within the Sirt1 locus were not associated with BMI suggesting that variation in trans-acting factors, rather than cis-acting SNPs, were responsible differences in Sirt1 expression. We further determined the prevalence of functional MC4R coding variants among all individuals living on the Gila River Indian Community. The MC4R exon was sequenced in 6761 individuals and six different mutations, which we demonstrated to cause reduced function in vitro, were found in 159 individuals (2.4%). Three mutations have been reported in other ethnic groups and 3 may potentially be unique to Pima Indians. During childhood (age 5 to 20 years), the slope of BMI increase was greater in individuals carrying an MC4R mutation as was the BMI z-score MC4R deficiency was also associated with an increased risk for developing type 2 diabetes, independent from an increased BMI, during childhood.